Relevance: Alcohol and other drug use are common among U.S. adolescents. Our prior studies found that adolescents with alcohol use disorders (AUD) show abnormalities on indices .of brain functioning, including neuropsychological testing, hippocampal volume, and functional magnetic resonance imaging (FMRI) response to cognitive tasks. We also found abnormalities on some of these measures related to risk factors for adolescent alcohol involvement. Thus, it is unclear if abnormalities observed in adolescents with AUD are caused by alcohol exposure, or predated the onset of heavy drinking. Description: This renewal project will follow youth initially characterized in the first funding period of R01 AA13419. At baseline, these youth are 12-14 year-olds free from any psychiatric disorder with, on average, one alcohol use experience, and half are at risk for AUD based on a family history of alcohol dependence. Baseline assessment includes neuropsychological testing, high resolution MRI, and FMRI acquisition during spatial working memory and inhibition tasks. In this competing renewal, we will expand the baseline sample from 128 to 285 youth, and follow these adolescents quarterly with interviews on substance use and general functioning. Each subject who initiates heavy drinking (defined as consuming >5 drinks on an occasion >5 times in a month), as well as a non-user matched for age, gender, and family history status, will be invited back to repeat the protocol on an annual basis for the duration of the 5-year project. Based on surveys in the school districts we recruit from (A/=5420), we anticipate that >20% (n>50) will initiate heavy drinking and 50% (n>125) will remain non-users as of the 4-year follow-up (i.e., by age 16-18). Aims: The goal of this study is to ascertain if indices of brain functioning (i.e., neuropsychological testing;hippocampal, prefrontal cortex, and cerebellar volumes;and FMRI response to spatial working memory and inhibition tasks in prefrontal and parietal regions) change after the onset of heavy drinking to a different degree than would be accounted for by normal adolescent neurodevelopment. We hypothesize that initiation of heavy drinking during adolescence will be associated with changes in brain structure and function, and that family history of AUD and gender will moderate this relationship. Other substance use (marijuana and nicotine) and other risk factors for SUD (externalizing behaviors, level of response to alcohol, and alcohol expectancies) will be evaluated as potential contributors to change in brain functioning. Based on our previous studies, we further hypothesize that baseline brain response patterns will significantly predict substance involvement in the following year.